LIF-IGF Axis Contributes to the Proliferation of Neural Progenitor Cells in Developing Rat Cerebrum.

In rodent models, leukemia inhibitory factor (LIF) is involved in cerebral development via the placenta, and maternal immune activation is linked to psychiatric disorders in the child. However, whether LIF acts directly on neural progenitor cells (NPCs) remains unclear. This study performed DNA microarray analysis and quantitative RT-PCR on the fetal cerebrum after maternal intraperitoneal or fetal intracerebral ventricular injection of LIF at day 14.5 (E14.5) and determined that the expression of insulin-like growth factors (IGF)-1 and -2 was induced by LIF. Physiological IGF-1 and IGF-2 levels in fetal cerebrospinal fluid (CSF) increased from E15.5 to E17.5, following the physiological surge of LIF levels in CSF at E15.5. Immunostaining showed that IGF-1 was expressed in the cerebrum at E15.5 to E19.5 and IGF-2 at E15.5 to E17.5 and that IGF-1 receptor and insulin receptor were co-expressed in NPCs. Further, LIF treatment enhanced cultured NPC proliferation, which was reduced by picropodophyllin, an IGF-1 receptor inhibitor, even under LIF supplementation. Our findings suggest that IGF expression and release from the NPCs of the fetal cerebrum in fetal CSF is induced by LIF, thus supporting the involvement of the LIF-IGF axis in cerebral cortical development in an autocrine/paracrine manner.

Long-term Outcomes of Non-syndromic and Syndromic Craniosynostosis: Analysis of Demographic, Morphologic, and Surgical Factors.

In this study, we analyzed the outcomes of patients (followed for 5-38 years, average 17.3 years) with craniosynostosis and evaluated their long-term prognosis. In all, 51 patients who underwent surgery for craniosynostosis between 1982 and 2015, including 12 syndromic and 39 non-syndromic cases, were included. The average age at the initial surgery was significantly lower in the syndromic group than that in the non-syndromic group (9.8 months old vs. 19.9 months, respectively). The surgical procedures did not significantly differ between the two groups, but repeat surgery was significantly more common in the syndromic group than in the non-syndromic group (4 children [30.8%] and 3 children [7.7%], respectively). The children requiring repeat surgery tended to be younger at the initial surgery than those who did not. Those patients who required repeat surgery did not have significantly different surgical procedures initially. The incidence of developmental retardation was 49.0% (43.5% in the non-syndromic group and 66.7% in the syndromic group), and only two children in the non-syndromic group displayed recovery. This study is the first to analyze the prognosis for patients who were followed for at least 5 years after cranioplasty. Repeat surgery was common, especially in syndromic patients. Severity of skull deformity and early initial surgery may be important factors determining the need for repeat surgery. Developmental retardation was also common, and improvement was rare even after surgery.

Anterior pituitary function in Rathke's cleft cysts versus nonfunctioning pituitary adenomas.

Although Rathke's cleft cysts (RCCs) are common sellar/parasellar lesions, studies examining pituitary function in patients with nonsurgical RCC are limited. This study aimed to clarify the importance of RCCs, including small nonsurgical ones, as a cause of hypopituitarism by determining the prevalence of pituitary hormone secretion impairment and its relationship to cyst/tumor size in patients with RCC and in those with nonfunctioning pituitary adenoma (NFA). We retrospectively investigated the basal levels of each anterior pituitary hormone, its responses in the stimulation test(s), and cyst/tumor size in patients with RCC (n = 67) and NFA (n = 111) who were consecutively admitted to our hospital for endocrinological evaluation. RCCs were much smaller than NFAs (median height, 12 vs. 26 mm). The prevalence of gonadotropin, PRL, and GH secretion impairment in RCC was lower in comparison to NFA (19% vs. 44%, 34% vs. 61%, and 24% vs. 46%, respectively), whereas the prevalence of TSH and ACTH secretion impairment was comparable (21-27% and 17-24%, respectively). A significant positive relationship between cyst/tumor size and number of impaired hormones was observed in both groups, but smaller cysts could cause hormone secretion impairment in RCC. Stimulation tests suggested that most hormone secretion impairment was attributable to the interrupted hypothalamic-pituitary axis in both groups. Therefore, RCC, even small ones, can cause pituitary dysfunction. Different mechanisms may underlie hypothalamic-pituitary interruption in RCC and NFA.

Pediatric meningioma with rhabdoid features developed at the site of skull fracture: illustrative case.

BACKGROUND: Pediatric meningiomas are rare, and only a few cases attributed to trauma and characterized by development at the site of bone fracture have been reported. Both pediatric and traumatic meningiomas have aggressive characteristics. OBSERVATIONS: An 11-year-old boy who sustained a head injury resulting from a left frontal skull fracture 8 years previously experienced a convulsive attack. Imaging revealed a meningioma in the left frontal convexity. Total removal of the tumor with a hyperostotic section was successfully achieved. Intraoperative investigation showed tumor invasion into the adjacent frontal cortex. Histologically, the surgical specimen revealed a transitional meningioma with brain invasion and a small cluster of rhabdoid cells. This led to a final pathological diagnosis of an atypical meningioma with rhabdoid features. The postoperative course was uneventful, and no recurrence of the tumor was found after 2 years without adjuvant therapy. LESSONS: This is the first report of a pediatric meningioma with rhabdoid features occurring at the site of a skull fracture. Meningiomas that contain rhabdoid cells without malignant features are not considered to be as aggressive as rhabdoid meningiomas. However, the clinical course must be carefully observed for possible long-term tumor recurrence.

A Case of Suprasellar Papillary Glioneuronal Tumor Mimicking Craniopharyngioma.

Papillary glioneuronal tumor (PGNT) is a low-grade biphasic neoplasm with astrocytic and neuronal differentiation. This tumor occurs most commonly in the frontal and temporal lobes, close to the ventricles, and rarely in the cerebellum, brainstem, and pineal gland. However, there has been no report of this tumor in the suprasellar region to date. In this paper, we report a case of PGNT in the suprasellar region in a 16-year-old girl. Magnetic resonance imaging (MRI) revealed a cystic tumor with calcification that progressed from the anterior skull base to the suprasellar and temporal regions. Preoperatively distinguishing this tumor from craniopharyngioma was difficult because of the patient's age, localization of the tumor, and neuroimaging results. This case showed a backward shift of the chiasma, which is observed in only 4.7% of craniopharyngioma, as well as normal endocrine findings. Endocrinological examination and an MRI evaluation of the chiasmal shift may be useful for discrimination.

Pituitary macroadenoma: Accuracy of apparent diffusion coefficient magnetic resonance imaging in grading tumor aggressiveness.

PURPOSE: The purpose of this study is to evaluate the accuracy of apparent diffusion coefficient magnetic resonance imaging in grading tumor aggressiveness using histogram apparent diffusion coefficient values. MATERIALS AND METHODS: Eighteen patients with surgically proved pituitary macroadenomas were included in this study. Diffusion-weighted imaging with single-shot echo-planar sequence at 3-T with a 32-channel head coil was performed with b values of 0 and 1000 s/mm2. Calculated apparent diffusion coefficient maps were generated, and a 3-D volume of interest was placed on the tumor while superimposing contrast-enhanced magnetic resonance images. All apparent diffusion coefficient values within the volume of interest were used to compute the average apparent diffusion coefficient of the tumor. The apparent diffusion coefficient values were binned to construct the apparent diffusion coefficient histogram. Using the histogram, the mean, percentiles, skewness, and kurtosis of the apparent diffusion coefficient of the entire tumor were computed. Apparent diffusion coefficient histogram parameters were compared with the MIB-1 index, invasiveness, and recurrence for grading tumor aggressiveness of pituitary adenomas. RESULTS: The skewness of the apparent diffusion coefficient histogram only showed significant differences among MIB-1 indices ( p = 0.030). All apparent diffusion coefficient histogram parameters showed no significant differences between negative and positive invasion. The skewness and kurtosis of the apparent diffusion coefficient histogram showed significant differences between positive and negative recurrence (skewness p = 0.011, kurtosis p = 0.011). Receiver-operating characteristics analysis between positive and negative recurrence showed that both skewness and kurtosis of the apparent diffusion coefficient achieved area under the curve at 0.967. CONCLUSION: Skewness and kurtosis of the apparent diffusion coefficient histogram were the predictive parameters for assessing tumor proliferative potential and recurrence of pituitary adenomas.

The clinicopathological analysis of receptor tyrosine kinases in meningiomas: the expression of VEGFR-2 in meningioma was associated with a higher WHO grade and shorter progression-free survival.

WHO grade II/III meningiomas recur frequently and there is currently no established molecular target therapy for meningioma. No previous studies have revealed the association between receptor tyrosine kinases (RTKs) and the recurrence of meningiomas. This study aims to elucidate the association between RTKs and the clinicopathological characteristics and recurrence of meningioma. We investigated the immunohistochemical expression of RTKs (VEGFR-1/2/3, PDGFR-alpha/beta and c-Kit) in 81 meningiomas (WHO grade I, n = 64, WHO grade II/III, n = 17) in 74 patients. Immunohistochemistry revealed that 29 WHO grade I (45%), 10 WHO grade II (77%), and 4 WHO grade III (100%) tumors were VEGFR-2-positive, and that the VEGFR-2 expression was significantly correlated with the WHO grade. In univariate analyses to investigate the clinicopathological factors associated with recurrence, Simpson grade IV/V resection, a larger tumor size, a high VEGFR-2 expression level, WHO grade II/III, a high Ki-67 expression level, and the non-expression of PgR were identified as significant factors. Furthermore, patients with VEGFR-2-positive meningiomas showed significantly shorter progression-free survival. In the multivariate analysis, WHO grade II/III and the location were significantly associated with recurrence. In conclusion, our study suggests that VEGFR-2 inhibitors might be one of the best candidates for molecular therapy against recurrent meningiomas.

Molecular mechanisms underlying the models of neurodevelopmental disorders in maternal immune activation relevant to the placenta.

The rapid rise in the prevalence of autism spectrum disorders (ASD) and other psychiatric disorders displaying similar traits has increased the need to elucidate their molecular mechanisms. Epidemiological studies have shown that maternal infection during mid-pregnancy is associated with increased risk of neurodevelopmental disorders such as ASD in offspring. Using maternal infection models, researchers have gathered evidence relevant to such disorders. A comprehensive summary of the changes in the brain structure, function, and behavior in offspring induced by maternal immune activation (MIA) has been reported. However, the molecular mechanisms underlying the association between MIA and improper brain development, which ultimately lead to neurodevelopmental disorders, have not been fully reviewed. This paper summarizes the currently known molecular mechanisms associated with the MIA model, with a special focus on the role of the placenta in fetal brain development.

Transsphenoidal Surgery for Elderly Patients with Acromegaly and Its Outcomes: Comparison with Younger Patients.

BACKGROUND: Elderly patients with acromegaly who have comorbidities may increasingly encounter perioperative complications; however, little data are available on the risks and outcomes of surgical treatment in these patients. We aimed to analyze and compare the results of transnasal transsphenoidal surgery (TTS) in elderly and younger patients. METHODS: Eighty-seven consecutive patients with acromegaly who underwent TTS were included. We divided the patients into elderly (≥65 years) and younger (<65 years) groups and compared clinical characteristics, anesthesia risk, and surgical outcomes in these 2 groups. RESULTS: The 87 patients included 24 (27.6%) in the elderly group and 63 (73.4%) in the younger group. Preoperative endocrinologic and radiologic assessments showed no significant differences between the 2 groups. Although a grade 3 American Society of Anesthesiologists Physical Status classification was more common in the elderly group (75% vs. 3%; P = 0.00001) owing to the severity of associated diseases, no significant between-group difference in perioperative complications was seen (17% vs. 6%; P = 0.142). Sixteen elderly patients and 45 younger patients achieved endocrinologic remission following surgery (67% vs. 71%; P = 0.426). The incidence rate of postoperative new pituitary deficit was similar in the elderly and younger groups (4% vs. 3%; P = 0.625). Approximately one-third of the elderly patients with diagnosed hypertension or diabetes mellitus tapered their medication after successful tumor removal. CONCLUSIONS: TTS can be considered a safe treatment for both younger and elderly patients with acromegaly. Successful tumor removal provided a significant improvement in comorbidities even in elderly patients with acromegaly.

Liquid chromatography-mass spectrometry with triazole-bonded stationary phase for N-methyl-D-aspartate receptor-related amino acids: development and application in microdialysis studies.

We aimed to monitor changes in the levels of amino acid neurotransmitters or neuromodulators simultaneously at the synaptic clefts of experimental animals. We developed a method for the simultaneous determination of the levels of amino acids, such as D-Ser, Gly, and L-Glu, which were involved in neurotransmission via the N-methyl-D-aspartate (NMDA) receptor, and other protein-constituted amino acids in a rat brain microdialysis (MD) sample. We used a liquid chromatography-mass spectrometry (LC-MS)/MS device equipped with a triazole-bonded column. The determination was achieved without using stable isotope-labeled compounds. We instead used suitable amino acid analogues as internal standards (ISs). We examined various analyte-IS combinations to improve reproducibility. We found a positive correlation (r = 0.720, **p < 0.0001) between relative standard deviation (%) of the area ratio and the analyte-IS retention time differences. Using the proposed method, we were able to accurately analyze trace amounts of amino acids in MD samples using ISs that were structurally similar to the analytes. Furthermore, we observed that the peripheral administration of S-methyl-L-cysteine, which was an inhibitor of the amino acid transporter Asc-1, caused some amino acid level changes in the rat brain. The proposed LC-MS/MS method can be applied in vivo to study the effects of novel therapeutic agents with monitoring the levels of amino acid neuromodulators, such as Glu, Gly, GABA, and D-Ser, in the brain. Graphical abstract LC-MS/MS analysis of amino acid enantiomers in microdialysis samples from rat striatum using triazole-bonded stationary phase.

Clinical characteristics of acromegalic patients with empty sella and their outcomes following transsphenoidal surgery.

PURPOSE: To analyze the clinical characteristics of acromegalic patients with empty sella (ES, herniation of the subarachnoid space within the sella turcica) and the impact of ES on transsphenoidal surgery in such patients. METHODS: Seventy-eight patients, newly diagnosed with acromegaly who underwent transsphenoidal surgery were included. ES was defined as the pituitary gland and adenoma occupying less than 50% of the sella turcica on midsagittal magnetic resonance (MR) imaging. RESULTS: Twelve patients (15.4%), predominantly female (10 women, p = .047), had ES in preoperative MR imaging. ES patients had smaller mean tumor diameter (6.3 mm) than non-ES patients (11.2 mm, p = .001). In preoperative MR imaging, occult adenoma was found in three (25%) ES and three (4.5%) non-ES patients (p = .044). Intraoperative cerebrospinal fluid (CSF) leakage was more frequent in the ES patients than in the non-ES patients (58.3 vs. 25.8%, p = .024). This led to an increased rate of sellar floor reconstruction using abdominal fat and/or postoperative lumber drainage in the ES patients (ES: 41.7 vs. non-ES: 16.7%, p = .063). Endocrinological remission after surgery was more frequent in the non-ES patients (72.7%) than in the ES patients (58.3%) (p = .248). CONCLUSIONS: Co-existence of acromegaly with ES is not rare, and is associated with occult adenoma, intra/postoperative CSF leakage, and a worse endocrinological outcome after transsphenoidal surgery; although, the underlying mechanism remains unclear.

[A Case of Cervical Internal Carotid Artery Occlusion Presenting with Subarachnoid Hemorrhage Caused by Rupture of Leptomeningeal Anastomosis].

A 71-year-old man was admitted to our hospital with a diagnosis of subarachnoid hemorrhage (SAH). Angiographies revealed neither aneurysms nor vascular anomalies. However, these images elucidated the occlusion of the left cervical internal carotid artery as well as developed leptomeningeal anastomoses through the ipsilateral posterior cerebral artery, which resulted in blood perfusing the ipsilateral middle and anterior cerebral artery territories. Because the localization of SAH coincided with the developed leptomeningeal anastomosis, we speculated that the rupture of the developed leptomeningeal anastomosis in the basal cistern was the cause of SAH. We performed superficial temporal and middle cerebral artery bypass surgery to prevent rebleeding and ischemic stroke. In patients with occlusion of the internal carotid artery, SAH induced by the rupture of aneurysm formed by hemodynamic stress was recognized. However, rupture of developed leptomeningeal anastomosis should be considered as a possible cause of SAH of unknown origin. (Received March 7, 2016; Accepted August 31, 2016; Published January 1, 2017).

Carotid artery protrusion and dehiscence in patients with acromegaly.

PURPOSE: Acromegaly is a systemic disease which causes multiple bony alterations. Some authors reported that acromegalic patients have risk factors for an intraoperative vascular injury due to the specific anatomical features of their sphenoid sinus. The objective of our study was to analyze the anatomic characteristics of sphenoid sinus in acromegalic patients compared with controls, by evaluation of computed tomography (CT) findings. METHODS: We examined 45 acromegalic (acromegaly group) and 45 non-acromegalic patients (control group) with pituitary adenomas who were matched for sex, age, height, tumor size, and cavernous sinus invasion (Knosp grade). Preoperative CT of the pituitary region including the sphenoid sinus was used to evaluate the following anatomic characteristics: type of sphenoid sinus (sellar or pre-sellar/conchal); intrasphenoid septa (non/single or multiple); carotid artery protrusion; carotid artery dehiscence; intercarotid distance. RESULTS: Sixteen acromegalic patients (35.5 %) and 6 controls (13.3 %) had carotid artery protrusion. Additionally, 10 acromegalic patients (22.2 %) and 3 controls (6.6 %) had carotid artery dehiscence. Carotid artery protrusion and dehiscence were more frequent in the acromegaly group than in control group (p = 0.013 and 0.035, respectively). Other anatomic characteristics (type of sphenoid sinus, intrasphenoid septa, and intracarotid distance) showed no significant differences between acromegaly and control groups. CONCLUSIONS: Our study suggests that carotid artery protrusion and dehiscence occur more frequently among acromegalic patients, compared with non-acromegalic patients. It is important for surgeons to be aware of these anatomic variations to avoid vital complications, such as carotid injuries, during surgery.

Rapid enlargement of an intracranial germ cell tumor after gonadotropin hormone therapy.

We report a case of an intracranial germ cell tumor (iGCT) that showed rapid enlargement after human chorionic gonadotropin (hCG) hormone therapy for pituitary hypogonadism. A 16-year-old boy presented with headache and was diagnosed with a suprasellar tumor. He was initially observed without surgery. Intranasal desmopressin therapy was started for central diabetes insipidus, but there was no change in the tumor size on MRI. The diagnosis of the tumor remained unknown for 4years. Levels of serum gonadotropin hormones (follicle-stimulating and luteinizing hormone) and testosterone progressively decreased, and the patient developed pituitary hypogonadism and complained about his undeveloped beard, lack of underarm hair, and erectile dysfunction. Intramuscular gonadotropin injection (hCG 5000U×2/week) was started at age 20. Eight months after the first gonadotropin injection, the MRI showed tumor growth with vivid enhancement. Craniotomy was performed and the tumor was partially resected. The histological diagnosis was immature teratoma. After surgery, the patient was treated with 5 cycles of chemotherapy with carboplatin and etoposide. He also received radiation therapy of 50Gy (20Gy tumor bed and 30Gy whole ventricles) to the residual tumor, after which the tumor decreased in size. We postulate that iGCT may be at risk of progression during hCG hormone therapy. Thus, careful monitoring is required for a patient with iGCT who receives this therapy.

[Possible Cerebral Infarction due to Multiple Segmental Cerebral Vasospasms after Carotid Artery Stenting: A Case Report].

A 62-year-old man was admitted due to consciousness disturbance and motor aphasia. Magnetic resonance (MR) images demonstrated watershed infarctions in the territory of the left middle cerebral artery, occlusion of the left internal carotid artery, and severe stenosis of the right internal carotid artery at the neck. He was treated with a recombinant tissue plasminogen activator. One month later, angiography revealed recanalization of the left internal carotid artery with residual severe stenosis at the neck. We attempted carotid artery stenting (CAS) on the left internal carotid artery, but could not pass the guide wire through the stenosis. Therefore, we performed CAS on the right carotid artery instead. At the second day after CAS, the patient showed consciousness disturbance, right hemiparesis, and motor aphasia. MR images showed a new infarction in the left cerebral hemisphere and bilateral multifocal segmental arterial constrictions. By keeping his blood pressure at a high enough level for one week, his symptoms were relieved, and MR images showed resolution of the vessel constrictions. From this case, we can conclude that this kind of multiple segmental vasospasms after CAS require contrasting treatments to those for hyperperfusion syndrome. Interventionalists should be aware of this condition and its treatments.

De Novo Aneurysm Formation Following Gamma Knife Surgery for Arteriovenous Malformation: A Case Report.

Background Stereotactic radiosurgery plays a critical role in the treatment of central nervous system neoplasm and cerebrovascular malformations. This procedure is purportedly less invasive, but problems occurring later including tumor formation, necrosis, and vasculopathy-related diseases have been reported. Clinical Presentation We report on a 65-year-old man who had experienced a de novo aneurysm in an irradiated field and an acute onset of right hemiparesis and aphasia. He had undergone gamma knife radiosurgery to treat an arteriovenous malformation 15 and 12 years prior, with 18 and 22 Gy marginal doses. At current admission, radiologic studies showed a de novo aneurysm in the irradiated field without recurrence of malformation. The aneurysm was resected. Histologic findings showed a disruption of the internal elastic lamina accompanied by fibrous degeneration. Conclusion Stereotactic radiosurgery is a promising treatment tool, but long-term risks have not been fully researched. The treatment procedure for benign lesions should be chosen prudently.

Determination of sex-based differences in serum γ-linolenic [corrected] acid and dihomo-γ-linolenic [corrected] acid using gas chromatography-mass spectrometry.

Because serum unsaturated fatty acids can provide useful information on disease diagnosis, the simultaneous determination of several fatty acids in small volumes of human serum would be beneficial for clinical applications. In the present study, serum fatty acids were extracted with n-heptane/chloroform from 10µL of serum collected from 26 healthy Japanese subjects (11 men, ages 23-37 years; 15 women, ages 18-37 years) after deproteinization with perchloric acid, derivatization to their methyl ester using p-toluenesulfonic acid as an acid catalyst, and subsequent separation and measurement by gas chromatography-mass spectrometry (GC-MS) in the selected ion monitoring mode. Nine types of fatty acids (palmitoleic acid [PLA], oleic acid [OA], linoleic [corrected] acid [LA], γ-linolenic acid [GLA], α-linolenic acid [ALA], dihomo-GLA [DGLA], arachidonic acid [AA], eicosapentaenoic acid [EPA], and docosahexaenoic acid [DHA]) were analyzed in the serum within 35 min by GC-MS. The concentrations of these fatty acids in serum ranged from 3.64±0.38µM (GLA) to 413±26.3 µM (LA). Among these nine fatty acids, GLA and DGLA levels were significantly lower in women than in men (p=0.0034 and 0.0012, respectively), suggesting that there may be sex-based differences in the biosynthetic production or metabolic processes of GLA and DGLA in humans.

The suppression of maternal-fetal leukemia inhibitory factor signal relay pathway by maternal immune activation impairs brain development in mice.

Recent studies in rodents suggest that maternal immune activation (MIA) by viral infection is associated with schizophrenia and autism in offspring. Although maternal IL-6 is though t to be a possible mediator relating MIA induced these neuropsychiatric disorders, the mechanism remains to be elucidated. Previously, we reported that the maternal leukemia inhibitory factor (LIF)-placental ACTH-fetal LIF signaling relay pathway (maternal-fetal LIF signal relay) promotes neurogenesis of fetal cerebrum in rats. Here we report that the maternal-fetal LIF signal relay in mice is suppressed by injection of polyriboinosinic-polyribocytidylic acid into dams, which induces MIA at 12.5 days post-coitum. Maternal IL-6 levels and gene expression of placental suppressor of cytokine signaling 3 (Socs3) increased according to the severity of MIA and gene expression of placental Socs3 correlated with maternal IL-6 levels. Furthermore, we show that MIA causes reduction of LIF level in the fetal cerebrospinal fluid, resulting in the decreased neurogenesis in the cerebrum. These findings suggest that maternal IL-6 interferes the maternal-fetal LIF signal relay by inducing SOCS3 in the placenta and leads to decreased neurogenesis.